Recently, it has been found that the bacterium Helicobacter pylori is a causative agent of human chronic gastritis, gastric and duodenal ulcers, as well as gastric adenocarcinoma in humans. (Blaser, Trends Microbiol., 7: 255-260 (1993)). H. pylori produces sialic acid-specific agglutinins enabling the bacterium to bind sialyl residue containing carbohydrates. However, studies using an in vitro adherence assay and other data have revealed that strains of H. pylori isolated from patients with acid peptic disease bind preferentially to the surface mucous and pit cells in the human gastric epithelium. This binding does not depend on the presence of sialic acid epitopes, but fucose residues constitute an essential recognition element of the epithelial cell's adhesion receptor (Falk et al., Proc. Natl. Acad. Sci. USA, 90: 2035-2039 (1993)). Additional studies have indicated that adherence of clinical isolates of H. pylori (P466 and WV229) to human gastric surface mucous cells occurs via the Le.sup.b antigen (Boren, et al., Science, 262: 1892-1895 (1993)), a fucosylated carbohydrate expressed by members of the pit cell lineage (Sakamoto, et al., Cancer Res., 49: 745-752 (1989); Falk, et al., Proc. Natl. Acad. Sci. USA, 90: 2035-2039 (1993). Solid phase binding and inhibition assays also indicated that the human H-1 blood group antigen, a monofucosylated carbohydrate that biochemically defines the blood group O phenotype, may also serve as a specific receptor for bacterial binding. In addition, such binding appears to be specific for the human gut, because binding to comparable cell lineages in the mouse, rat and dog is either significantly weaker, as in Sprague-Dawley rats, or not detectable, as in FVB/N mice. Thus, H. pylori has been found to preferentially bind to distinct molecules, such as the Le.sup.b and H-1 antigens, and to sialic acid residues found on glycoproteins on the surface of gastric epithelial cells (Boren et al., Science, 262: 1892-1895 (1993); Evans et al., J. Bacteriol., 175: 674-683 (1993)).
Combined chemotherapy with antibiotics (tetracycline and metronidazole), H.sub.2 blockers (ranitidine), and bismuth subsalicylate have been used with some success for treating H. pylori-associated ulcers, although relapse remains a clinical problem (Graham, et al., Ann. Int. Med., 116: 705-708 (1991)). The exact mechanism by which this bacterium causes chronic active gastritis, gastric and duodenal ulcers and gastric adenocarcinoma remains unclear. It is well documented that H. pylori infection of gut epithelial is strongly correlated with development of gastric adenocarcinoma (six to twelve times increased risk according to Forman, et al., Lancet, 341: 1359-1363 (1993)). Gastric adenocarcinoma is the fourth leading cause of cancer death worldwide (Levine and Price, In Helicobacter pylori infection (Northfield, Mendall, and Goggin eds.), pp. 88-89 (Kluwer Acad. Publ., Boston (1993)).
An effective alternative to antibiotic therapy that is curative and/or prevents H. pylori-associated disease has not been developed. An animal model for H. pylori infection of the stomach and/or intestinal tract would thus be highly desirable not only for detailed in vivo studies of H. pylori-associated diseases caused by wild type and genetically engineered strains, but also for the systematic development and screening for new antibiotics, non-antibiotic compounds, and various other therapies employing natural products and chemically synthesized compositions of matter which are effective in blocking H. pylori adhesion, infection, or the subsequent development of H. pylori-associated disease states. In addition, an animal model for H. pylori infection in the stomach and intestinal tract could be used in developing and assessing effective gene therapies against H. pylori-associated gastritis, ulcers, carcinomas, and presumably other H. pylori-associated diseases, as well as examining the efficacy of various methods used to immunize the host so as to prevent or ameliorate H. pylori infection.
It is therefore an object of the present invention to provide an animal model for H. pylori infection and pathogenesis.
It is a further object of the present invention to provide a method for screening and evaluating compounds which block H. pylori adhesion to gut endothelium or ameliorate the effects of H. pylori binding on the pathogenesis of acid peptic disease.